Sex differences in striatal-mediated cognitive and sensorimotor behaviors have been demonstrated for decades. These behaviors and the function of the striatum itself are sensitive to the action of the steroid sex hormone 17?-estradil (estradiol) in females but not males. Likewise, many disorders linked to the striatum are sensitive to estradiol action and/or show a sex bias in incidence and/or severity. Remarkably, the mechanisms and extent to which estradiol organizes and then modulates the striatal neuron electrophysiological properties that ultimately enable these changes in function and behavior are not well understood, providing the rationale for this proposal. The overall goal of this proposal is to fill this critical knowledge gap, working towards our long-term goal of understanding how striatal intrinsic and synaptic electrophysiology can be modulated by steroid sex hormones and genetic sex to generate sex differences in function and pathologies. To do this we will focus on the predominant and output neurons of the striatum: the medium spiny neurons (MSNs), and use rats as a model system. MSN action potentials constitute the output of striatal processing. Thus all striatal sex differences must ultimately influence MSN electrical properties to influence behavior. One key electrical property is intrinsic membrane excitability, which governs the ability of a neuron to produce action potentials in response to electrical and synaptic input. We recently discovered that MSN excitability is increased in prepubertal females compared to males, and that excitability is rapidly modulated by estradiol. Increased female MSN excitability was not blocked by glutamatergic and GABAergic receptor antagonists, meaning that increased excitability in female MSNs is not mediated by classical fast neurotransmission. Likewise, no sex differences were detected in excitatory synaptic input. Since sex differences in MSN excitability occur pre-puberty, this raises the exciting possibility that this is organized before adulthood, is re-programmed during puberty, and acutely modulated by adult estradiol action. The central hypothesis of this project, which is based upon these initial findings, is this: estradiol organizes and then acutely regulates MSN excitability vi sex specific mechanisms. We will test this hypothesis over the following three specific aims: 1) Elucidate the mechanism underlying organizational actions of estradiol on MSN excitability; 2) Delineate the mechanism underlying rapid actions of estradiol on MSN excitability; and 3) Determine the functional impact of estradiol actions on the excitability of specific MSN subtypes. These studies will have an important positive impact because they will address the neural electrophysiological mechanisms underlying estradiol action in striatal function. This will be an important advancement in fundamental knowledge that is potentially useful for understanding the mechanisms underlying sex differences in striatal pathologies and generating new targets for sex-specific therapies. More broadly, this research will help lead to a better understanding of the relationship between estradiol, genetic sex, and neuron electrophysiological properties.